- 學位論文
設計並合成新穎的腺苷衍生物用於探討腺苷受體的生物活性
Design and Synthesis of Novel Adenosine Derivatives to Target Adenosine Receptor
摘要
腺苷受體會表現於許多不同的細胞表面上，並以細胞外的腺苷濃度作為訊號原，將訊息往細胞內部傳遞，進而影響細胞的活性表現。腺苷A2A受體(adenosine A2A receptor, A2AR)在之前的研究中發現，患有亨丁頓舞蹈症(Huntington’s disease, HD)的小鼠細胞內突變的huntingtin蛋白 (mutant huntingtin, mHtt)會因為A2AR活化而減少沉澱的程度，進而減緩HD的進程。 傳統中草藥天麻(Gastrodia elata, GE)常用於與神經有關的疾病。從天麻中分離出的N6-(4-羥苯甲基)腺苷[N6-(4-hydroxybenzyl)adenine riboside (8, T1-11)]，發現其具有活化A2AR的活性。因此實驗室同仁以T1-11為基礎，合成了一系列腺苷N6修飾與核醣5ʹ修飾的衍生物以測試活性。其中N6-(5-溴噻吩-2-甲基)腺苷[N6-((5-bromothien-2-yl)methyl)adenine riboside (15)]具有非常高的生物可利用度(bioavailability, BA)，在小鼠實驗中展現了相當好的結果。為了理解不同取代的噻吩是否會影響腺苷衍生物的活性，我合成了N6-((4-bromothien-2-yl)methyl)adenine riboside (18)；與此同時，我們也優化了15的合成方法，使得產率從36%提高至83%而且不用層析方法純化產物。 除了腺苷N6的修飾外，我們也針對腺苷內核糖五號碳上的羥基以胺基酸甲酯做修飾。我們成功在T1-11的核醣五號碳上做了許多不同的衍生物，藉此調整T1-11的生物特性。除此之外，此方法也成功地將T1-11與我們有興趣的生物大分子結合，也有令人振奮的結果出現。
並列摘要
Adenosine receptors (ARs) are expressed on the membrane of various cells. These receptors take the intercellular adenosine concentration as the signal to regulate the activity of cells. It has been reported that activation of adenosine A2A receptor (A2AR) can slow down the progression of Huntington’s disease by decreasing the precipitation of mutant huntingtin (mHtt), and thus reducing the neuron death caused by the mHtt. Activation of A2AR may be a good strategy for treatment of Huntington’s disease. Gastrodia elata is widely used in Chinses herbal medicine for the treatment of diseases related to central nervous system (CNS). N6-(4-Hydroxybenzyl)adenine riboside (8, T1-11) was isolated from G. elata and found to be neuroprotective by activating A2AR. A series of T1-11 analogs with modification at N6-adenine and 5ʹ-hydroxyl group of ribose has been synthesized in our lab. Among these analogs, N6-((5-bromothien-2-yl)methyl)adenine riboside (15) was found to possess good bioavailability (BA) and improve Huntington’s disease in mice model. In addition, N6-((4-bromothien-2-yl)methyl)adenine riboside (18) was synthesized to study the effect of substituents on the thiophene ring. The synthetic procedure of 15 was also optimized to improve the yield from 36% to 83% with minimal purification steps. Besides the modification at N6-adenine of T1-11, the analogs having the ribose 5ʹ-hydroxyl group conjugated to amino acid methyl ester were synthesized to explore new compounds with better biological properties. The conjugates of T1-11 with proteins and peptides were synthesized through the same strategy. Some conjugated products did show promising results for drug development.